Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome

Frontiers in Genetics

卷:10

Delia Yubero²  Juan D. Ortigoza-Escobar³  Marti Iriondo³  Maria M. O’Callaghan³  Rafael Artuch³  Angels García-Cazorla³  Julio Alberto Andrés-Sanz⁴  Javier Amezcua-Gil⁴  Paula Gaudó⁴  Sonia Emperador⁶  Nuria Garrido-Pérez⁶  Eduardo Ruiz-Pesini⁶  Ana Fernández-Marmiesse⁷  María Pilar Bayona-Bafaluy⁸  Julio Montoya⁸  Mercedes Gil-Campos⁹ 

[1] CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Madrid, Spain;

[2] Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain;

[3] Clinical Biochemistry, Genetics, Pediatric Neurology and Neonatalogy Departments, Institut de Recerca Sant Joan de Déu, Barcelona, Spain;

[4] Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain;

[5] Disease Group, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), Santiago de Compostela University—IDIS, Santiago de Compostela, Spain;

[6] Fundación ARAID, Universidad de Zaragoza, Zaragoza, Spain;

[7] Genomes&

[8] Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain;

[9] Metabolism Unit, Reina Sofia University Clinical Hospital, Institute Maimónides of Biomedicine Investigation of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain;

关键词: mitochondrial disease;    encephalomyopathic mtDNA depletion syndrome 13;    F-box leucine-rich repeat protein 4;    mitochondrial DNA;    mtDNA depletion;    mtDNA transcription;   

DOI  :  10.3389/fgene.2019.01300

来源: DOAJ

【 摘 要 】

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation.

【 授权许可】

Unknown